Thrombin belongs to the group of serine proteases and plays a central part in the blood coagulation cascade as terminal enzyme. Both the intrinsic and the extrinsic coagulation cascade lead, via several amplifying stages, to the production of thrombin from prothrombin. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and platelet aggregation, which in their turn enhance thrombin formation by the binding of platelet factor 3 and coagulation factor XIII as well as a whole series of highly active mediators.
The formation and effect of thrombin are central events in the production both of white, arterial and of red, venous thrombi and therefore potentially effective points of attack for drugs. Thrombin inhibitors contrast with heparin in being able completely to inhibit, independently of cofactors, simultaneously the effects of thrombin both in the coagulation cascade and on platelets. They are able to prevent in the acute phase thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis and to serve as anticoagulants in extracorporeal circulation (heart-lung machine, hemodialysis). They can also be used generally for thrombosis prophylaxis, for example after surgical interventions.
It is known that synthetic arginine derivatives influence the enzymic activity of thrombin by interacting with the active serine residue of the protease. Peptides based on Phe-Pro-Arg in which the N-terminal amino acid is in the D form have proved to be particularly beneficial. D-Phe-Pro-Arg isopropyl ester has been described as a competitive thrombin inhibitor (C. Mattson et al., Folia Haematol. 109 (1982) 43-51).
Derivatization of the C-terminal arginine to the aldehyde leads to an enhancement of the inhibitory action. Thus, a large number of arginals able to bind the hydroxyl group of the xe2x80x9cactivexe2x80x9d serine as hemiacetal have been described (EP 185,390, 479,489, 526,877, 542,525; WO 93 15 756, 93 18 060).
The thrombin inhibitory activity of peptide ketones, fluorinated alkyl ketones and of keto esters, boric acid derivatives, phosphoric esters and xcex1-keto carboxamides can likewise be explained by this serine interaction (EP 118,280, 195,212, 362,002, 364,344, 410,411, 471,651, 589,741, 293,881, 503,203, 504,064, 530,167; WO 92 07 869; 94 08 941).
DE 31 08 810 and WO 93 11 152 describe xcfx89-aminoalkylguanidine di-peptides.
The peptide 4-amidinophenylglycinephosphonate diphenyl esters described by J. Oleksyszyn et al. in J. Med. Chem. 37 (1994) 226-231 are irreversible thrombin inhibitors with inadequate selectivity for other serine proteases.
EP 601,459 and WO 94/29336, which are not prior publications, describe thrombin inhibitory peptides.
The present invention relates to novel thrombin inhibitors, to the preparation thereof and to the use thereof for controlling diseases.
The present invention relates to compounds of the formula 
and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings: 
where in all the abovementioned A radicals the xcex1-NH or xcex1-NH2 group can be mono- or disubstituted by C1-12-alkyl, phenyl-C1-4-alkylene, X12OCxe2x80x94C1-6-alkylene, X12OCxe2x80x94C1-6-alkylcarbonyl, -xcex1- or xcex2-naphthyl-C1-4-alkylene, C1-12-alkylcarbonyl, phenyl-C1-4-alkylcarbonyl, C1-7-alkoxycarbonyl, phenyl-C1-5-alkoxycarbonyl, -xcex1- or xcex2-naphthyl-C1-4-alkylcarbonyl-, C1-6-alkylaminocarbonyl or phenyl-C1-4-alkylaminocarbonyl
also A: X1xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, X1xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94
X15xe2x80x94(CH2)fxe2x80x94SO2xe2x80x94(f=0,1,2,3,4, X15=a phenyl or xcex1- or xcex2-naphthyl radical which is unsubstituted or substituted by 1-3 CH3 and/or CH3O groups, or one of the radicals 
X18xe2x80x94Oxe2x80x94COxe2x80x94C1-4-alkylene-COxe2x80x94 (X18=H, C1-4-alkyl),
C1-12-alkyl-COxe2x80x94, C1-10-alkyl-NHxe2x80x94CO-phenyl-C1-4-alkylene-NHxe2x80x94COxe2x80x94, xcex1- or xcex2-naphthyl-COxe2x80x94 or 
xe2x80x83(X18=H or C1-4-alkyl,
xe2x80x83X19=H, C1-6-alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl)
R1: H or C1-4-alkyl
R2: H or C1-4-alkyl
R3: H, C1-8-alkyl, phenyl, phenyl-C1-4-alkylene, CH2OH, xe2x80x94COxe2x80x94X20, xe2x80x94COxe2x80x94COxe2x80x94X20, (X20=H, C1-4-alkoxy, C1-4-alkyl, phenyl, phenyl-C1-4-alkylene, phenyl-C1-4-alkoxy, CF3, C2F5, an N-terminally linked natural amino acid, CH2OH, xe2x80x94CH2xe2x80x94Oxe2x80x94C1-4-alkyl, NHxe2x80x94(C1-4-alkylene)-phenyl or NHxe2x80x94C1-6-alkyl),
m: 0,1,2 or 3
D: phenylene on which (CH2)m and (NH)n are linked in the para or meta position to one another and which can be substituted in the ortho position to (CH2)m by F, Cl, Br, HOxe2x80x94CH2xe2x80x94, OH, NH2, NO2, C1-4-alkoxy, C1-6-alkyl or COX21 (X21=H, C1-4-alkyl, C1-4-alkoxy, OH, NH2, NHxe2x80x94C1-4-alkyl) xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94COxe2x80x94X21 or xe2x80x94(CH2)1-3xe2x80x94COxe2x80x94X21,
pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, on which (CH2)m and (NH)n are linked in the para or meta position to one another and which can be substituted in the ortho position to (CH2)m by F, Cl, Br, OH, NH2, C1-4-alkoxy or C1-4-alkyl,
1,4- or 1,3-cyclohexylene, in which one CH2 group in the ortho position to (CH2)m can be replaced by NH, O, S or SO, or piperidinylene which is connected in the 3 or 4 position to the nitrogen to (CH2)m, and in which the nitrogen atom itself carries the C(xe2x95x90NH)NHR4 group,
n: 0 or 1
R4: H, xe2x80x94COxe2x80x94C1-20-alkyl, xe2x80x94COxe2x80x94Oxe2x80x94C1-20-alkyl, OH or NH2.
The alkyl radicals present in the formula I may be straight-chain or branched.
Preferred compounds of the formula I are those where the substituents have the following meanings: 
(X4=H, F, Cl, Br, CF3, C1-4-alkyl, OH, OCH3, NO2, phenyl, preferably H, F, Cl, Br, CH3, t-butyl, OH, OCH3, NO2, X5=H, F, Cl, Br, CH3, OH, OCH3, phenyl, preferably H, F, OH, OCH3, phenyl, X6=H, F, Cl, Br, CH3, OH, OCH3, preferably H, F, OH, OCH3, X7=H, F, X8=H, F), 
R1: H, CH3 
R2: H
R3: H, CH3, CHO, COCF3, COC2F5, COxe2x80x94CH2OH, COxe2x80x94CH3, COxe2x80x94CH2-phenyl, CH2OH,
R4: H, OH, NH2 
m: 0, 1
a preferred group of D building blocks is 
preferred building blocks of the combination xe2x80x94(CH2)m-D-(NH)nxe2x80x94 in the general formula I are: 
Particularly preferred compounds of the formula I are those in which the substituents have the following meanings: 
Among the particularly preferred compounds, the following combinations should be emphasized, where A and B have the meanings described as particularly preferred: 
The following substances are mentioned by way of example:
1. Boc-(D)-Phe-Pro-NH-(4-Am)-2-phenethyl
2. H-(D)-Phe-Pro-NH-(4-Am)-2-phenethyl
3. Boc-Phe-Pro-NH-pAmb
4. H-Phe-Pro-NH-pAmb
5. Boc-(D)-Phe-Pro-NH-pAmb
6. Ac-(D)-Phe-Pro-NH-pAmb
7. H-(D)-Phe-Pro-NH-pAmb
8. H-(D)-Phe-Pro-N(Me)-pAmb
9. Me-(D)-Phe-Pro-NH-pAmb
10. Z-Me-(D)-Phe-Pro-NH-pAmb
11. HOOCxe2x80x94CH2-(D)-Phe-Pro-NH-pAmb
12. MeOOCxe2x80x94CH2-(D)-Phe-Pro-NH-pAmb
13. t-BuOOCxe2x80x94CH2-(Boc)-(D)-Phe-Pro-NH-pAmb
14. EtOOC-(D)-Phe-Pro-NH-pAmb
15. Boc-(D)-Phe-Pro-NH-mAmb
16. H-(D)-Phe-Pro-NH-mAmb
17. Z-(D)-Phe-Pro-(D,L)(4-Am)-PhgOH
18. Z-(D)-Phe-Pro-(D,L)(4-Am)-PhgOMe
19. H-(D)-Phe-Pro-(D,L)(4-Am)-Phgxe2x80x94OH
20. Boc-(D)-Phe-Pro-(4-Am)-PhgCH2Ph
21. H-(D)-Phe-Pro-(4-Am)-PhgCH2Ph
22. H-(D)-Phe-Pro-NH-pAm-[(D,L)-xcex1-Me]-benzyl
23. Me-(D)-Phe-Pro-(D or L)(4-Am)-Phg"psgr"[CH2xe2x80x94OH]/a
24. Me-(D)-Phe-Pro-(D or L)(4-Am)-Phg"psgr"[CH2xe2x80x94OH]/b
25. Boc-(D)-Phe(4-F)-Pro-NH-pAmb
26. H-(D)-Phe(4-F)-Pro-NH-pAmb
27. Boc-(D)-Phe(4-Cl)-Pro-NH-pAmb
28. H-(D)-Phe(4-Cl)-Pro-NH-pAmb
29. Boc-(D,L)-Phe(4-Br)-Pro-NH-pAmb
30. H-(D,L)-Phe(4-Br)-Pro-NH-pAmb
31. H-(D)-Phe(4-OH)-Pro-NH-pAmb
32. Boc-(D)-Phe(4-MeO)-Pro-NH-pAmb
33. H-(D)-Phe(4-MeO)-Pro-NH-pAmb
34. Boc-(D,L)-Phe(4-EtO)-Pro-NH-pAmb
35. H-(D,L)-Phe(4-EtO)-Pro-NH-pAmb
36. Boc-(D)-Phe(4-BzlO)-Pro-NH-pAmb
37. H-(D)-Phe(4-BzlO)-Pro-NH-pAmb
38. Boc-(D,L)-Phe(4-Et)-Pro-NH-pAmb
39. H-(D,L)-Phe(4-Et)-Pro-NH-pAmb
40. Boc-(D,L)-Phe(4-iPr)-Pro-NH-pAmb
41. H-(D,L)-Phe(4-iPr)-Pro-NH-pAmb
42. Z-(D)-Phe(4-tBuO)-Pro-NH-pAmb
43. H-(D)-Phe(4-tBuO)-Pro-NH-pAmb
44. Boc-(D,L)-Phe(4-tBu)-Pro-NH-pAmb
45. H-(D,L)-Phe(4-tBu)-Pro-NH-pAmb
46. H-(D,L)-Phe(4-Ph)-Pro-NH-pAmb
47. Boc-(D,L)-Phe(4-n-Bu)-Pro-NH-pAmb
48. H-(D,L)-Phe(4-n-Bu)-Pro-NH-pAmb
49. Boc-(D)-Phe(4-COOMe)-Pro-NH-pAmb
50. H-(D)-Phe(4-COOMe)-Pro-NH-pAmb
51. H-(D)-Phe(4-NO2)-Pro-NH-pAmb
52. Boc-(D,L)-Phe(3-F)-Pro-NH-pAmb
53. H-(D,L)-Phe(3-F)-Pro-NH-pAmb
54. Boc-(D,L)-Phe(3-Cl)-Pro-NH-pAmb
55. H-(D,L)-Phe(3-Cl)-Pro-NH-pAmb
56. H-(D,L)-Phe(3-OH)-Pro-NH-pAmb
57. Boc-(D,L)-Phe(3-MeO)-Pro-NH-pAmb
58. H-(D,L)-Phe(3-MeO)-Pro-NH-pAmb
59. Boc-(D,L)-Phe(3-PhO)-Pro-NH-pAmb
60. H-(D,L)-Phe(3-PhO)-Pro-NH-pAmb
61. Boc-(D,L)-Phe(3-Me)-Pro-NH-pAmb
62. H-(D,L)-Phe(3-Me)-Pro-NH-pAmb
63. H-(D,L)-Phe(3-Ph)-Pro-NE-pAmb
64. Boc-(D,L)-Phe(3-CF3)-Pro-NH-pAmb
65. H-(D,L)-Phe(3-CF3)-Pro-NH-pAmb
66. Boc-(D,L)-Phe(2-F)-Pro-NH-pAmb
67. H-(D,L)-Phe(2-F)-Pro-NH-pAmb
68. Boc-(D,L)-Phe(2-Cl)-Pro-NH-pAmb
69. H-(D,L)-Phe(2-C1)-Pro-NH-pAmb
70. Boc-(D,L)-Phe(2-OH)-Pro-NH-pAmb
71. H-(D,L)-Phe(2-OH)-Pro-NH-pAmb
72. Boc-(D,L)-Phe(2-Meo)-Pro-NH-pAmb
73. H-(D,L)-Phe(2-MeO)-Pro-NH-pAmb
74. Boc-(D,L)-Phe(2-Me)-Pro-NH-pAmb
75. H-(D,L)-Phe(2-Me)-Pro-NH-pAmb
76. Boc-(D,L)-Phe(2-iPr)-Pro-NH-pAmb
77. H-(D,L)-Phe(2-iPr)-Pro-NH-pAmb
78. Boc-(D,L)-Phe(2-Ph)-Pro-NH-pAmb
79. H-(D,L)-Phe(2-Ph)-Pro-NH-pAmb
80. Boc-(D,L)-Phe(3,4-(F)2)-Pro-NH-pAmb
81. H-(D,L)-Phe(3,4-(F)2)-Pro-NH-pAmb
82. Boc-(D,L)-Phe(3,4-(Cl)2)-Pro-NH-pAmb
83. H-(D,L)-Phe(3,4-(Cl)2)-Pro-NH-pAmb
84. Boc-(D,L)-Phe(3-Cl-4-MeO)-Pro-NH-pAmb
85. H-(D,L)-Phe(3-Cl-4-MeO)-Pro-NH-pAmb
86. Boc-(D,L)-Phe(3-Cl-4-EtO)-Pro-NH-pAmb
87. H-(D,L)-Phe(3-Cl-4-EtO)-Pro-NH-pAmb
88. H-(D,L)-Phe(3,4-(MeO)2)-Pro-NH-pAmb
89. Boc-(D,L)-Phe(3,4-(Me)2)-Pro-NH-pAmb
90. H-(D,L)-Phe(3,4-(Me)2)-Pro-NH-pAmb
91. Boc-(D,L)-Phe(3-Me-4-iPr)-Pro-NH-pAmb
92. H-(D,L)-Phe(3-Me-4-iPr)-Pro-NH-pAmb
93. Boc-(D,L)-Phe(2,3-(MeO)2)-Pro-NH-pAmb
94. H-(D,L)-Phe(2,3-(MeO)2)-Pro-NH-pAmb
95. Boc-(D,L)-Phe(2,5-(MeO) 2)-Pro-NH-pAmb
96. H-(D,L)-Phe(2,5-(MeO)2)-Pro-NH-pAmb
97. Boc-(D,L)-Phe(3,5-(MeO)2)-Pro-NH-pAmb
98. H-(D,L)-Phe(3,5-(MeO)2)-Pro-NH-pAmb
99. Boc-(D,L)-Phe(3,4,5-(MeO)3)-Pro-NH-pAmb
100. H-(D,L)-Phe(3,4,5-(MeO)3)-Pro-NH-pAmb
101. Boc-(D,L)-Phe(2,4,6-(Me)3)-Pro-NH-pAmb
102. H-(D,L)-Phe(2,4,6-(Me)3)-Pro-NH-pAmb
103. Boc-(D)-xcex1Nal-Pro-NH-pAmb
104. H-(D)-xcex1Nal-Pro-NH-pAmb
105. H-(D)-xcex2Nal-Pro-NH-pAmb
106. Boc-(D,L)-xcex1Ngl-Pro-NH-pAmb
107. H-(D,L)-xcex1Ngl-Pro-NH-pAmb
108. Boc-(D,L)-xcex2Ngl-Pro-NH-pAmb
109. H-(D,L)-xcex2Ngl-Pro-NH-pAmb
110. H-(D,L)-1-Tic-Pro-NH-pAmb
111. Boc-(D)-3-Tic-Pro-NH-pAmb
112. H-(D)-3-Tic-Pro-NH-pAmb
113. 1-Icc-Pro-NH-pAmb
114. Boc-(D,L)-2-Tgl-Pro-NH-pAmb
115. H-(D,L)-2-Tgl-Pro-NH-pAmb
116. Boc-(D,L)-2-Tal-Pro-NH-pAmb
117. H-(D,L)-2-Tal-Pro-NH-pAmb
118. Boc-(D)-Phg-Pro-NH-pAmb
119. H-(D)-Phg-Pro-NH-pAmb
120. Boc-(D,L)-Phg(4-MeO)-Pro-NH-pAmb
121. H-(D,L)-Phg(4-MeO)-Pro-NH-pAmb
122. Boc-(D)-Chg-Pro-NH-pAmb
123. H-(D)-Chg-Pro-NH-pAmb
124. EtOOC-(D)-Chg-Pro-NH-pAmb
125. HOOCxe2x80x94CH2-(D)-Chg-Pro-NH-pAmb
126. tBuOOCxe2x80x94CH2-(D)-Chg-Pro-NH-pAmb
127. Boc-(D)-Cha-Pro-NH-pAmb
128. Me-(D)-Cha-Pro-NH-pAmb
129. Me-(Z)-(D)-Cha-Pro-NH-pAmb
130. N,N-Me2-(D)-Cha-Pro-NH-pAmb
131. Boc-(D)-Trp(Boc)-Pro-NH-pAmb
132. H-(D)-Trp-Pro-NH-pAmb
133. Boc-(D,L)-Dpa-Pro-NH-pAmb
134. H-(D or L)-Dpa-Pro-NH-pAmb/a
135. H-(D or L)-Dpa-Pro-NH-pAmb/b
136. EtOOC-(D or L)-Dpa-Pro-NH-pAmb/a
137. EtOOC-(D or L)-Dpa-Pro-NH-pAmb/b
138. HOOCxe2x80x94CH2-(D or L)-Dpa-Pro-NH-pAmb/a
139. HOOCxe2x80x94CH2-(D or L)-Dpa-Pro-NH-pAmb/b
140. Boc-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/a
141. Boc-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/b
142. H-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/a
143. H-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/b
144. EtOOC-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/a
145. EtOOC-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/b
146. HOOCxe2x80x94CH2-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/a
147. HOOCxe2x80x94CH2-(D or L)-Dpa(4,4xe2x80x2-(Cl)2)-Pro-NH-pAmb/b
148. H-(D or L)-Dch-Pro-NH-pAmb/a
149. H-(D or L)-Dch-Pro-NH-pAmb/b
150. Boc-(D)-Val-Pro-NH-pAmb
151. H-(D)-Val-Pro-NH-pAmb
152. Boc-(D)-Leu-Pro-NH-pAmb
153. H-(D)-Leu-Pro-NH-pAmb
154. Boc-(D)-Gly(xcex1-tBu)-Pro-NH-pAmb
155. H-(D)-Gly (xcex1-tBu)-Pro-NH-pAmb
156. Boc-(D)-Ala(xcex2-tBu)-Pro-NH-pAmb
157. H-(D)-Ala(xcex2-tBu)-Pro-NH-pAmb
158. H-(D or L)-Msu-Pro-NH-pAmb/a
159. H-(D or L)-Msu-Pro-NH-pAmb/b
160. Boc-(Cyclo)Leu-Pro-NH-pAmb
161. H-(Cyclo)Leu-Pro-NH-pAmb
162. Boc-Gly-Pro-NH-pAmb
163. H-Gly-Pro-NH-pAmb
164. Ph-CH2xe2x80x94CO-Gly-Pro-NH-pAmb
165. Ph-CH2xe2x80x94CH2xe2x80x94CO-Gly-Pro-NH-pAmb
166. Ph-CH2-Gly-Pro-NH-pAmb
167. xcex2-Naphthyl-CH2-Gly-Pro-NH-pAmb
168. [3,4-(MeO)2-phenyl]-Ch2-Gly-Pro-NH-pAmb
169. Ph-CH2xe2x80x94CO-Pro-NH-pAmb
170. Ph-CH2xe2x80x94CH2xe2x80x94CO-Pro-NH-pAmb
171. Ph-CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CO-Pro-NH-pAmb
172. xcex1-Naphthyl-CO-Pro-NH-pAmb
173. xcex2-Naphthyl-CO-Pro-NH-pAmb
174. xcex1-Naphthyl-CH2xe2x80x94CO-Pro-NH-pAmb
175. xcex2-Naphthyl-CH2xe2x80x94CO-Pro-NH-pAmb
176. xcex2-Naphthyl-SO2-Pro-NH-pAmb
177. p-Tol-SO2-Pro-NH-pAmb
178. Ph-CH2xe2x80x94CH2xe2x80x94SO2-Pro-NH-pAmb
179. H-Asp-Pro-NH-pAmb
180. Boc-Asp(OMe)-Pro-NH-pAmb
181. H-Asp(OMe)-Pro-NH-pAmb
182. Ph-CH2xe2x80x94CO-Asp(OMe)-Pro-NH-pAmb
183. Ph-CH2xe2x80x94CH2xe2x80x94CO-Asp(OMe)-Pro-NH-pAmb
184. (n-Pr)2CHxe2x80x94CO-Asp-Pro-NH-pAmb
185. H-Asp(OBzl)-Pro-NH-pAmb
186. (n-Pr)2CHxe2x80x94CO-Asp(OBzl)-Pro-NH-pAmb
187. Ph-CH2xe2x80x94CO-Asp-Pro-NH-pAmb
188. Ph-CH2xe2x80x94CH2xe2x80x94CO-Asp-Pro-NH-pAmb
189. (n-Pr)2CHxe2x80x94CO-Asp(OMe)-Pro-NH-pAmb
190. Z-(D)-Asp(OMe)-Pro-NH-pAmb
191. H-(D)-Asp-Pro-NH-pAmb
192. Z-(D)-Asp(OtBu)-Pro-NH-pAmb
193. H-(D)-Asp(OtBu)-Pro-NH-pAmb
194. Boc-(D)-Asp(OBzl)-Pro-NH-pAmb
195. H-(D)-Asp(OBzl)-Pro-NH-pAmb
196. Z-(D)-Glu(OtBu)-Pro-NH-pAmb
197. H-(D)-Glu(OtBu)-Pro-NH-pAmb
198. H-(D)-Glu-Pro-NH-pAmb
199. (D)-Ph-CH2xe2x80x94CHOHxe2x80x94CO-Pro-NH-pAmb
200. (D)-Man-Pro-NH-pAmb
201. Boc-(D)-Phe-Aze-NH-pAmb
202. H-(D)-Phe-Aze-NH-pAmb
203. Boc-(D)-Phe-(D,L)-Pic-NH-pAmb
204. H-(D)-Phe-(D or L)-Pic-NH-pAmb/a
205. H-(D)-Phe-(D or L)-Pic-NH-pAmb/b
206. Boc-(D)-Phe-(D,L/trans)-Pic(4-Me)-NH-pAmb
207. H-(D)-Phe-(D,L/trans)-Pic(4-Me)-NH-pAmb
208. Boc-(D)-Phe-Pyr-NH-pAmb
209. H-(D)-Phe-Pyr-NH-pAmb
210. Boc-(D)-Phe-Hyp(O-tBu)-NH-pAmb
211. H-(D)-Phe-Hyp-NH-pAmb
212. Boc-(D)-Phe-(Me)Val-NH-pAmb
213. H-(D)-Phe-(Me)Val-NH-pAmb
214. Boc-(D)-Phe-Val-NH-pAmb
215. H-(D)-Phe-Val-NH-pAmb
216. Boc-(D)-Phe-Tia-NH-pAmb
217. H-(D)-Phe-Tia-NH-pAmb
218. H-(D)-Phe-Pro-NH-3-(6-am)-pico
219. Boc-(D)-Chg-Pro-NH-3-(6-Am)-pico
220. H-(D)-Chg-Pro-NH-3-(6-Am)-pico
221. HOOCxe2x80x94CH2-(D)-Chg-Pro-NH-3-(6-Am)-pico
222. HOOCxe2x80x94CH2-(D)-Chg-Pyr-NH-3-(6-Am)-pico
223. HOOCxe2x80x94CH2-(D)-Chg-2-Phi-NH-3-(6-Am)-pico
224. HOOCxe2x80x94CH(Me)-(D)-Chg-Pro-NH-3-(6-Am)-pico
225. Boc-(D)-Phe-Pro-NH-3-(2-Me-6-Am)-pico
226. H-(D)-Phe-Pro-NH-3-(2-Me-6-Am)-pico
227. Boc-(D)-Chg-Pro-NH-3-(2-Me-6-Am)-pico
228. H-(D)-Chg-Pro-NH-3-(2-Me-6-Am)-pico
229. tBuOOCxe2x80x94CH2-(D)-Chg-Pro-NH-3-(2-Me-6-Am)-pico
230. HOOCxe2x80x94CH2-(D)-Chg-Pro-NH-3-(2-Me-6-Am)-pico
231. MeOOCxe2x80x94CH2-(D)-Chg-Pro-NH-3-(2-Me-6-Am)-pico
232. Boc-(D)-Chg-Pro-NH-2-(5-Am)-pico
233. H-(D)-Chg-Pro-NH-2-(5-Am)-pico
234. HOOCxe2x80x94CH2-(D)-Chg-Pro-NH-2-(5-Am)-pico
235. HOOCxe2x80x94CH2-(D)-Chg-Pro-NH-5-(2-Am)-pym
236. (D)-Man-Pro-NH-4-(1-Am)-pip
237. Boc-(D)-Phe-Pro-NH-pHamb
238. H-(D)-Phe-Pro-NH-pHamb
239. Boc-(D)-Phe-Pro-NH-(2-MeO)-pAmb
240. H-(D)-Phe-Pro-NH-(2-MeO)-pAmb
241. Boc-(D)-Phe(4-Meo)-Pro-NH-(2-MeO)-pAmb
242. H-(D)-Phe(4-MeO)-Pro-NH-(2-MeO)-pAmb
243. HOOCxe2x80x94CH2-(D)-Phe(4-MeO)-Pro-NH-(2-MeO)-pAmb
244. Boc-(D)-Chg-Pro-NH-(2-MeO)-pAmb
245. H-(D)-Chg-Pro-NH-(2-MeO)-pAmb
246. HOOCxe2x80x94CH2-(D)-Chg-Pro-NH-(2-MeO)-pAmb
247. Boc-(D)-Chg-Aze-NH-(2-MeO)-pAmb
248. H-(D)-Chg-Aze-NH-(2-MeO)-pAmb
249. Boc-(D)-Chg-Pro-NH-(2-iPrO)-pAmb
250. H-(D)-Chg-Pro-NH-(2-iPrO)-pAmb
251. Boc-(D)-Chg-Pro-NH-(2-Cl)-pAmb
252. H-(D)-Chg-Pro-NH-(2-Cl)-pAmb
253. H-(D)-Phe-Pro-(D,L)(4-Am)-PhgOMe
254. Boc-(D,L)-Phe(3-OH)-Pro-NH-pAmb
255. BOC-(D,L)-1-Tic-Pro-NH-pAmb
256. H-(D)-Chg-Pro-NH-3-(2-MeO-6-Am)-pico
The compounds of the formula I may be present as such or in the form of their salts with physiologically tolerated acids. Examples of such acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malonic acid, succinic acid, hydroxysuccinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
The novel compounds can be used for the therapy and prophylaxis of all diseases in which thrombin plays a part. These are, in particular, thromboembolic disorders such as myocardial infarct, peripheral arterial occlusive disease, deep vein thrombosis, pulmonary embolism and stroke. They can additionally be used to prevent reocclusion after arterial vessels have been opened by mechanical methods or lysis.
The substances are furthermore suitable for preventing the formation of thrombin by directly inhibiting kallikrein.
Their particular advantage is that they are also effective after oral administration.
The invention also relates to the following substances of the formula II which are valuable intermediates for preparing the compounds I: 
in which R1, R2 and R3 have the meanings stated for formula I, and
R5: is H, C1-4-alkoxy-COxe2x80x94 or phenyl-C1-3-alkoxy-COxe2x80x94,
R6: is cyano, amidino or guanidino in the m or p position to C(R2,R3) and
p: is 1,2 or 3.
The abbreviations used in the description and the examples have the following meanings: